title: Tumor necrosis factor-neuropeptide Y cross talk regulates inflammation, epithelial barrier functions, and colonic motility.
abstract: BACKGROUND
  Neuro-immune interactions play a significant role in regulating the severity of inflammation. Our previous work demonstrated that neuropeptide Y (NPY) is upregulated in the enteric nervous system during murine colitis and that NPY knockout mice exhibit reduced inflammation. Here, we investigated if NPY expression during inflammation is induced by tumor necrosis factor (TNF), the main proinflammatory cytokine.
  
  
  METHODS
  Using primary enteric neurons and colon explant cultures from wild type and NPY knockout (NPY(-/-)) mice, we determined if NPY knockdown modulates TNF release and epithelial permeability. Further, we assessed if NPY expression is inducible by TNF in enteric neuronal cells and mouse model of experimental colitis, using the TNF inhibitors-etanercept (blocks transmembrane and soluble TNF) and XPro1595 (blocks soluble TNF only).
  
  
  RESULTS
  We found that enteric neurons express TNF receptors (TNFR1 and R2). Primary enteric neurons from NPY(-/-) mice produced less TNF compared with wild type. Further, TNF activated NPY promoter in enteric neurons through phospho-c-Jun. NPY(-/-) mice had decreased intestinal permeability. In vitro, NPY increased epithelial permeability through phosphatidyl inositol-3-kinase (PI3-K)-induced pore-forming claudin-2. TNF inhibitors attenuated NPY expression in vitro and in vivo. TNF inhibitor-treated colitic mice exhibited reduced NPY expression and inflammation, reduced oxidative stress, enhanced neuronal survival, and improved colonic motility. XPro1595 had more protective effects on neuronal survival and motility compared with etanercept.
  
  
  CONCLUSIONS
  We demonstrate a novel TNF-NPY cross talk that modulates inflammation, barrier functions, and colonic motility during inflammation. It is also suggested that selective blocking of soluble TNF may be a better therapeutic option than using anti-TNF antibodies.
authors.affiliation: *Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, Georgia; †Department of Physiology, University of Toronto, Ontario, Canada; ‡Department of Biology, Center for Diagnostics and Therapeutics, Suite 790 Petit Science Center, Georgia State University, Atlanta, Georgia; §Veterans Affairs Medical Center, Decatur, Georgia; ‖Division of Gastroenterology, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts; and ¶Department of Pathology and Laboratory Medicine, and **Department of Physiology, Emory University, Atlanta, Georgia.
authors.forename: Bindu
authors.initials: B
authors.lastname: Chandrasekharan
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jeppsson
authors.forename: Stefan
authors.initials: S
authors.lastname: Pienkowski
authors.forename: Denise D
authors.initials: DD
authors.lastname: Belsham
authors.forename: Shanthi V
authors.initials: SV
authors.lastname: Sitaraman
authors.forename: Didier
authors.initials: D
authors.lastname: Merlin
authors.forename: Efi
authors.initials: E
authors.lastname: Kokkotou
authors.forename: Asma
authors.initials: A
authors.lastname: Nusrat
authors.forename: Malu G
authors.initials: MG
authors.lastname: Tansey
authors.forename: Shanthi
authors.initials: S
authors.lastname: Srinivasan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D002463:Cell Membrane Permeability; D047369:Chromatin Immunoprecipitation; D003092:Colitis / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004553:Electric Conductivity; D017615:Enteric Nervous System / Q000378:metabolism / Q000473:pathology; D005769:Gastrointestinal Motility / Q000502:physiology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D061346:Laser Capture Microdissection; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009478:Neuropeptide Y / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016207:Cytokines; D009478:Neuropeptide Y; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases